As recently reviewed by us, SERT-deficient +/- and -/- mice have gene-proportionate increases in extracellular fluid serotonin concentrations, i.e., 5- or 7-fold excesses respectively over wildtype +/+ mice. At the same time, SERT -/- mice have a marked deficit of intracellular, releasable serotonin. Continuing advances have been made in our studies of serotonin-related toxic reactions, including the serotonin syndrome. Most commonly, this toxicity occurs as a side effect in humans treated with certain antidepressant and anti-anxiety drugs. Importantly, its milder forms contribute to reduced therapeutic efficacy or a requirement to interrupt treatment in some individuals treated with SRIs. Our earlier studies exploring this behavioral and temperature-related syndrome in SERT-deficient mice revealed a genetic vulnerability to a markedly exaggerated serotonin syndrome when these mice were exposed to the metabolic precursor of serotonin, 5-HTP, or to other serotonergic drugs such as the monoamine oxidase-inhibiting (MAO-I) antidepressant tranylcypromine. In addition to the serotonin syndrome behavioral changes, exaggerated alterations in temperature responses were also found in SERT- and MAO-deficient mice. We are now further extending these studies to include dopamine transporter (DAT) knockout mice to further explicate the unusual behavioral feature, some resembling compulsive, stereotyped behaviors related to human obsessive-compulsive disorder (OCD). These findings in these mouse genetic models suggest the likelihood that humans with lower-expressing SLC6A4 SS, SLg and LgLg genotypes, or other SERT or MAO or DAT variants that may lead to 50-80% decreases in binding sites or transport function, may be at higher risk to develop behavioral neurotoxicity. Of special note, it is likely that relatively mild serotonin syndrome occurrence may contribute to early discontinuation of SRIs and other side effects during SRI treatment of neuropsychiatric patients that are strongly associated with the lower-expressing SLC6A4, SLC6A3 or SLC1A1 genotypes. Given this transgenic mouse data and human SLC6A4 and MAO polymorphism data, we have formed an international collaborative effort - Genes Involved in Serotonin Toxicity or GISETTO - in which we are examining functional variants in the multiple serotonin (SLC6A4, MAOA) and drug metabolizing gene groups (e.g., CYP2D6) in hospitalized individuals developing serotonin toxicity and other serotonin-related toxicities, both retrospectively and prospectively, in collaboration with our Newcastle, AZ colleagues. Understanding these genetic mechanisms will improve serotonergic drug safety and efficacy by identifying patients whose response to drugs might be genetically compromised, and thereby might be at risk of adverse and potentially life threatening drug reactions. SERT and MAO provide intriguing examples of likely mouse-human congruence in genetic vulnerability to serotonin toxicity. Functional variants exist in additional genes that can also be postulated to confer vulnerability to serotonin neurotoxicity, for example, serotonin receptor genes. This past year, we extended our studies of transporter systems by generating both conditional EAAC3 knockout and transgenic overexpressing mice. Comprehensive behavioral and other studies were initiated this year. A report about these mice was published in abstract from this year (Moya PR et al., 2013). Overall, the data accumulated by our Lab, as referenced below and previously, support the use of different genetically modified mice as vulnerability models for humans with SERT, MAO, EAAC3 and other gene variants with regard to gene-gene and gene-environment interactions that contribute to human diseases and the pharmacologic treatment of multiple psychiatric disorders. Citations numbers of other papers that have referenced our scientific reports number over 35,000 as of August, 2013. The protocol number for this report is LCS 04.